The Nontuberculous Mycobacteria

Definition

Nontuberculous mycobacteria generally include the growing number of mycobacteria other than Mycobacterium tuberculosis and its close relatives ( Chapter 299 ) and M. leprae ( Chapter 301 ). Other names that have been used include atypical mycobacteria , mycobacteria other than tuberculosis , and environmental mycobacteria . Over 190 species of nontuberculous mycobacteria are now known, and the number continues to grow as DNA sequencing identifies additional species.

Epidemiology

As a group, the nontuberculous mycobacteria are ubiquitous in soil and water. They are often found in certain animals (e.g., M. avium subspecies paratuberculosis cause Johne disease in cattle, whereas M. avium or M. genavense cause avian tuberculosis), but they rarely cause disease in humans. Human-to-human transmission of nontuberculous mycobacteria is rare, but M. abscessus subspecies massiliense has caused outbreaks of infection in cystic fibrosis centers.

Because these infections are not reported to health agencies and because their identification is sometimes problematic, reliable data on incidence and prevalence are lacking. Worldwide, documented infections with nontuberculous mycobacteria are increasing, and isolates of nontuberculous mycobacteria have exceeded those for M. tuberculosis in the United States for many years. In patients with cystic fibrosis ( Chapter 77 ), for example, rates of clinical nontuberculous mycobacterial infection range up to 40% in older patients, but even more patients harbor the organism. Differentiating active disease from commensal harboring of the organism remains problematic. Other patients, including patients with bronchiectasis ( Chapter 78 ), also have elevated but undefined rates of nontuberculous mycobacterial infection. The bulk of nontuberculous mycobacterial disease in North America is due to M. kansasii , M. avium complex (MAC), and M. abscessus .

Predisposing factors for lung infections include underlying lung disease, such as bronchiectasis ( Chapter 78 ), pneumoconiosis ( Chapter 81 ), chronic obstructive pulmonary disease ( Chapter 76 ), primary ciliary dyskinesia ( Chapter 78 ), and cystic fibrosis ( Chapter 77 ). Bronchiectasis and nontuberculous mycobacterial infection often coexist and progress in tandem, thereby making causality difficult to determine. Patients with pulmonary alveolar proteinosis ( Chapter 79 ) are prone to pulmonary nontuberculous mycobacterial and Nocardia infections ( Chapter 306 ), likely reflecting their association with anti–granulocyte-macrophage colony-stimulating factor (anti–GM-CSF) autoantibodies and impaired alveolar macrophage function.

M. avium complex infection most commonly occurs in women in their sixth or seventh decades. When compared with male smokers with upper lobe cavitary disease, who tend to carry the very same single strain of M. avium complex indefinitely, nonsmoking females with nodular bronchiectasis tend to have several strains simultaneously, which also change over the course of their disease process.

Esophageal motility disorders such as achalasia ( Chapter 124 ) have been associated with pulmonary disease, especially that caused by rapidly growing nontuberculous mycobacteria such as M. abscessus . Numerous outbreaks of skin infections caused by rapidly growing mycobacteria have been due to skin contamination from instruments used for surgical procedures (especially cosmetic surgery), injections, and other procedures.

Pathobiology

Exposure to nontuberculous mycobacteria is essentially universal, but disease is rare, so normal host defenses must be highly effective. For M. avium complex, the portal of entry that leads to dissemination is the bowel, with subsequent spread to bone marrow and the blood stream.

CD4 ⁺ T lymphocytes are key effectors against nontuberculous mycobacteria, and patients with advanced human immunodeficiency virus (HIV) infection are especially susceptible to disseminated mycobacterial infection ( Chapter 358 ). Specific mutations in the interferon (IFN)-γ/interleukin (IL)-12 synthesis and response pathways also predispose to dissemination, but only about 70% of non-HIV patients with disseminated infection have an identifiable genetic mutation. Autoantibodies to IFN-γ mimic genetic defects in the pathway.

Mycobacteria are typically phagocytosed by macrophages, which respond with the production of IL-12, a heterodimer composed of p35 and p40 moieties that together constitute IL-12p70 ( E-Fig. 300-1 ). IL-12 activates T lymphocytes and natural killer (NK) cells through binding to its receptor (composed of IL-12Rβ1 and IL-12Rβ2/IL-23R) and results in phosphorylation of STAT4 (signal transducer and activator of transcription 4). IL-12 stimulation leads to production and secretion of IFN-γ, which activates neutrophils and macrophages to produce reactive oxidants and increase major histocompatibility complex display and Fc receptors. IFN-γ signals through its receptor (composed of IFN-γR1 and IFN-γR2), thereby leading to phosphorylation of STAT1, which in turn regulates IFN-γ–responsive genes such as those for the production of IL-12 and tumor necrosis factor (TNF)-α. Therefore, the positive feedback loop between IFN-γ and IL-12/IL-23 is pivotal in the immune response to mycobacteria and other intracellular infections (most importantly Salmonella [ Chapter 284 ], Histoplasma [ Chapter 308 ], and Coccidioides [ Chapter 308 ]). The advent of potent TNF-α inhibitors such as infliximab, adalimumab, certolizumab, etanercept, and golimumab ( Chapter 29 ) has provided the ability to neutralize this critical cytokine to treat inflammatory disease but at the expense of an increased risk for developing mycobacterial and fungal infections.

Nontuberculous mycobacterial osteomyelitis is especially common in patients who have dominant negative mutations in IFN-γR1. Adult-onset disseminated disease may be associated with GATA2 deficiency (monocytopenia, NK and B cell cytopenia). Some patients with disseminated disease, especially women from southeast Asia, have high-titer autoantibodies to IFN-γ.

Clinical Manifestations